The striatum is a key component of the basal ganglia circuitry controlling action selection and habit learning (Maia and Frank, 2011; Yin and Knowlton, 2006; herein incorporated by reference in their entireties). It is widely assumed that activity-dependent alterations in the strength of corticostriatal glutamatergic synapses formed on principal spiny projection neurons (SPNs) underlies striatal learning (Lerner and Kreitzer, 2011; Surmeier et al., 2009; Wickens et al., 2003; herein incorporated by reference in their entireties). Not only are these synapses important for normal learning, their dysregulation has been implicated in a number of psychomotor diseases, including Parkinson's disease (PD) (Gerfen and Surmeier, 2011; Kreitzer and Malenka, 2007; Kurz et al., 2010; Shen et al., 2008; herein incorporated by reference in their entireties).
One of the most important modulators of corticostriatal synapses is dopamine (DA) (Calabresi et al., 2007; Gerfen and Surmeier, 2011; Kreitzer and Malenka, 2007; Lovinger, 2010; Shen et al., 2008; herein incorporated by reference in their entireties). By virtue of their differential expression of G-protein linked DA receptors, striatal indirect pathway SPNs (iSPNs) and direct pathway SPNs (dSPNs) respond to DA in contrasting ways. In D2 receptor (D2R) expressing iSPNs, DA promotes the induction of Hebbian long-term depression (LTD) at corticostriatal synapses and opposes A2a adenosine receptor (A2aR) mediated induction of long-term potentiation (LTP) (Shen et al., 2008; Surmeier et al., 2009; herein incorporated by reference in their entireties). This is accomplished by bidirectionally regulating adenylyl cyclase (AC) through Gi-coupled D2Rs and Golf-coupled A2aRs (Augustin et al., 2014; Higley and Sabatini, 2010; Lerner et al., 2010; herein incorporated by reference in their entireties).
In dSPNs, Golf-coupled D1 DA receptors (D1Rs) are necessary for the induction of LTP. D1R signaling also disrupts the induction of Hebbian LTD (Fino et al., 2010; Pawlak and Kerr, 2008; Shen et al., 2008; Yagishita et al., 2014; herein incorporated by reference in their entireties). But it is unclear whether there is a receptor that is homologous to the D2R in dSPNs that promotes LTD and opposes LTP induction.
The Gi-coupled M4 muscarinic receptor (M4R) is the most abundant striatal muscarinic receptor and it is preferentially expressed in dSPNs where it is clustered near axospinous glutamatergic synapses (Bernard et al., 1992; Di Chiara et al., 1994; Hersch et al., 1994; Izzo and Bolam, 1988; herein incorporated by reference in their entireties). Giant cholinergic interneurons (ChIs) have dense terminal fields that overlap those of DA neurons, allowing M4R suppression of D1R signaling through AC (Jeon et al., 2010; Sánchez et al., 2009; herein incorporated by reference in their entireties). Nevertheless, the role of M4Rs in regulating synaptic plasticity in dSPNs has not been determined.
One of the unmet clinical needs for PD patients is a strategy for reducing levodopa-induced dyskinesia (LID). Levodopa (L-DOPA) treatment is a mainstay for early and mid-stage PD patients. Although it is initially effective in alleviating symptoms, as the disease progresses, L-DOPA becomes less effective and the dose required to achieve symptomatic benefit rises. In most patients, high doses of L-DOPA produce unwanted dyskinetic movements. Many lines of evidence suggest that aberrant D1R-dependent synaptic plasticity is a major factor (Cenci and Konradi, 2010; Feyder et al., 2011; Heiman et al., 2014; Jenner, 2008; Picconi et al., 2003; herein incorporated by reference in their entireties). In particular, it is thought that repeated L-DOPA treatment heightens D1R signaling, leading to pathological LTP of corticostriatal synapses and inappropriately timed or scaled dSPN activity (Picconi et al., 2003; herein incorporated by reference in its entirety). Antagonizing D1Rs is not a viable therapeutic strategy because it diminishes the symptomatic benefit of L-DOPA treatment. Hence, identifying an alternative means of normalizing D1R signaling would provide relief from LID.